Severe Combined Immunodeficiency

Joining the movement to fight rare diseases

/ Kevin McCormack / 4 Comments

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It’s hard to think of something as being rare when it affects up to 30 million Americans and 300 million people worldwide. But the truth is there are more than 6,000 conditions – those affecting 200,000 people or fewer – that are considered rare.  

Today, February 28th, is Rare Disease Day. It’s a day to remind ourselves of the millions of people, and their families, struggling with these diseases. These conditions are also called or orphan diseases because, in many cases, drug companies were not interested in adopting them to develop treatments.

At the California Institute for Regenerative Medicine (CIRM), we have no such reservations. In fact last Friday our governing Board voted to invest almost $12 million to support a clinical trial for IPEX syndrome. IPEX syndrome is a condition where the body can’t control or restrain an immune response, so the person’s immune cells attack their own healthy tissue. This leads to the development of Type 1 diabetes, severe eczema, damage to the small intestines and kidneys and failure to thrive. It’s diagnosed in infancy, most of those affected are boys, and it is often fatal.

Taylor Lookofsky (who has IPEX syndrome) and his father Brian

IPEX is one of two dozen rare diseases that CIRM is funding a clinical trial for. In fact, more than one third of all the projects we fund target a rare disease or condition. Those include:

Some might question the wisdom of investing hundreds of millions of dollars in conditions that affect a relatively small number of patients. But if you see the faces of these patients and get to know their families, as we do, you know that often agencies like CIRM are their only hope.

Dr. Maria Millan, CIRM’s President and CEO, says the benefits of one successful approach can often extend far beyond one rare disease.

“Children with IPEX syndrome clearly represent a group of patients with an unmet medical need, and this therapy could make a huge difference in their lives. Success of this treatment in this rare disease presents far-reaching potential to develop treatments for a larger number of patients with a broad array of immune disorders.”

CIRM is proud to fund and spread awareness of rare diseases and invites you to watch this video about how they affect families around the world.

CIRM-funded stem cell clinical trial patients: Where are they now?

/ Esteban Cortez / Leave a comment
Ronnie with his parents Pawash Priyank and Upasana Thakur.

Since its launch in 2004, the California Institute for Regenerative Medicine (CIRM) has been a leader in growing the stem cell and regenerative medicine field while keeping the needs of patients at the core of its mission. 

To date, CIRM has:  

  • Advanced stem cell research and therapy development for more than 75 diseases. 
  • Funded 76 clinical trials with 3,200+ patients enrolled. 
  • Helped cure over 40 children of fatal immunological disorders with gene-modified cell therapies. 

One of these patients is Ronnie, who just days after being born was diagnosed with severe combined immunodeficiency (SCID), a rare immune disorder that is often fatal within two years. 

A recent photo of Ronnie enjoying a day at the beach.

Fortunately, doctors told his parents about a CIRM-funded clinical trial conducted by UC San Francisco and St. Jude Children’s Hospital. Doctors took some of Ronnie’s own blood stem cells and, in the lab, corrected the genetic mutation that caused the condition. They then gave him a mild dose of chemotherapy to clear space in his bone marrow for the corrected cells to be placed and to grow. Over the next few months, the blood stem cells created a new blood supply and repaired Ronnie’s immune system. He is now a happy, healthy four-year-old boy who loves going to school with other children. 

Evie Junior participated in a CIRM-funded clinical trial in 2020. Photo: Jaquell Chandler

Another patient, Evie Junior, is pioneering the search for a cure for sickle cell disease: a painful, life-threatening condition.  

In July of 2020, Evie took part in a CIRM-funded clinical trial where his own blood stem cells were genetically modified to overcome the disease-causing mutation. Those cells were returned to him, and the hope is they’ll create a sickle cell-free blood supply. Evie hasn’t had any crippling bouts of pain or had to go to the hospital since his treatment.

To demonstrate treatment efficacy, study investigators will continue to monitor the recovery of Evie, Ronnie, and others who participate in clinical trials. 

CIRM’s new strategic plan seeks to help real life patients like Ronnie and Evie by optimizing its clinical trial funding partnership model to advance more therapies to FDA for approval.  

In addition, CIRM will develop ways to overcome manufacturing hurdles for the delivery of regenerative medicine therapies and create Community Care Centers of Excellence that support diverse patient participation in the rapidly maturing regenerative medicine landscape. Stay tuned as we cover these goals here on The Stem Cellar. 

To learn more about CIRM’s approach to deliver real world solutions for patients, check out our new 5-year strategic plan.  

Looking back and looking forward: good news for two CIRM-supported studies

/ Kevin McCormack / 1 Comment
Dr. Rosa Bacchetta on the right with Brian Lookofsky (left) and Taylor Lookofsky after CIRM funded Dr. Bacchetta’s work in October 2019. Taylor has IPEX syndrome

It’s always lovely to end the week on a bright note and that’s certainly the case this week, thanks to some encouraging news about CIRM-funded research targeting blood disorders that affect the immune system.

Stanford’s Dr. Rosa Bacchetta and her team learned that their proposed therapy for IPEX Syndrome had been given the go-ahead by the Food and Drug Administration (FDA) to test it in people in a Phase 1 clinical trial.

IPEX Syndrome (it’s more formal and tongue twisting name is Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome) is a life-threatening disorder that affects children. It’s caused by a mutation in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood. 

Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.

This approach has already been accorded an orphan drug and rare pediatric disease designation by the FDA (we blogged about it last year)

Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.

Under the FDA’s rare pediatric disease designation program, the FDA may grant priority review to Dr. Bacchetta if this treatment eventually receives FDA approval. The FDA defines a rare pediatric disease as a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and affects fewer than 200,000 people in the U.S.

Congratulations to the team and we wish them luck as they begin the trial.

Dr. Donald Kohn, Photo courtesy UCLA

Someone who needs no introduction to regular readers of this blog is UCLA’s Dr. Don Kohn. A recent study in the New England Journal of Medicine highlighted how his work in developing a treatment for severe combined immune deficiency (SCID) has helped save the lives of dozens of children.

Now a new study in the journal Blood shows that those benefits are long-lasting, with 90% of patients who received the treatment eight to 11 years ago still disease-free.

In a news release Dr. Kohn said: “What we saw in the first few years was that this therapy worked, and now we’re able to say that it not only works, but it works for more than 10 years. We hope someday we’ll be able to say that these results last for 80 years.”

Ten children received the treatment between 2009 and 2012. Nine were babies or very young children, one was 15 years old at the time. That teenager was the only one who didn’t see their immune system restored. Dr. Kohn says this suggests that the therapy is most effective in younger children.

Dr. Kohn has since modified the approach his team uses and has seen even more impressive and, we hope, equally long-lasting results.

Celebrating a young life that almost wasn’t

/ Kevin McCormack / Leave a comment

Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.

Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.

At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.  

Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.

He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.

SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.

The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.

Ja’Ceon on his first day at pre-K. He loved it.

CIRM-catalyzed spinout files for IPO to develop therapies for genetic diseases

/ Yimy Villa / 1 Comment

Graphite Bio, a CIRM-catalyzed spinout from Stanford University that launched just 14 months ago has now filed the official SEC paperwork for an initial public offering (IPO). The company was formed by CIRM-funded researchers Matt Porteus, M.D., Ph.D. and Maria Grazia Roncarolo, M.D.

Six years ago, Dr. Porteus and Dr. Roncarolo, in conjunction with Stanford University, received a CIRM grant of approximately $875K to develop a method to use CRISPR gene editing technology to correct the blood stem cells of infants with X-linked severe combined immunodeficiency (X-SCID), a genetic condition that results in a weakened immune system unable to fight the slightest infection.

Recently, Dr. Porteus, in conjunction with Graphite, received a CIRM grant of approximately $4.85M to apply the CRISPR gene editing approach to correct the blood stem cells of patients with sickle cell disease, a condition that causes “sickle” shaped red blood cells. As a result of this shape, the cells clump together and clog up blood vessels, causing intense pain, damaging organs, and increasing the risk of strokes and premature death. The condition disproportionately affects members of the Black and Latin communities.

CIRM funding helped Stanford complete the preclinical development of the sickle cell disease gene therapy and it enabled Graphite to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA), one of the last steps necessary before conducting a human clinical trial of a potential therapy. Towards the end of 2020, Graphite got the green light from the FDA to conduct a trial using the gene therapy in patients with sickle cell disease.

In a San Francisco Business Times report, Graphite CEO Josh Lehrer stated that the company’s goal is to create a platform that can apply a one-time gene therapy for a broad range of genetic diseases.

Paving the Way

/ Kevin McCormack / Leave a comment

When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.

The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.

The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.

Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.

Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.

CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.

Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.

It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.

Stem cell therapy for deadly childhood immune disorder goes four for four

/ Kevin McCormack / Leave a comment

The gold standard for any new therapy in the U.S. is approval by the Food and Drug Administration (FDA). This approval clears the therapy for sale and often also means it will be covered by insurance. But along the way there are other designations that can mean a lot to a company developing a new approach to a deadly disease.

That’s what recently happened with Mustang Bio’s MB-107. The therapy was given Orphan Drug Designation for the treatment of X-linked Severe Combined Immunodeficiency (SCID) also known as “bubble baby disease”, a rare but deadly immune disorder affecting children. This is the same therapy that CIRM is funding in a clinical trial we’ve blogged about in the past.  

Getting Orphan Drug Designation can be a big deal. It is given to therapies intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. It comes with some sweet incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. And, if the product becomes the first in its class to get FDA approval for a particular disease, it is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

This is not the first time Mustang Bio’s MB-107 has been acknowledged as a potential gamechanger. It’s also been given three other classifications both here in the US and in Europe.

  • Rare Pediatric Disease Designation: this also applies to treatments for diseases affecting fewer than 200,000 people in the US that have the potential to provide clinically meaningful benefits to patients. It provides the company with a “voucher” that they can use to apply for priority review for another therapy they are developing. The hope is that this will encourage companies to develop treatments for rare childhood diseases that might not otherwise be profitable.
  • Regenerative Medicine Advanced Therapy (RMAT) designation: this allows for faster, more streamlined approvals of regenerative medicine products
  • Advanced Therapy Medicinal Product classification: this is granted by the European Medicines Agency (EMA) to medicines that are based on genes, tissues or cells and can offer groundbreaking opportunities for the treatment of disease.

Of course, none of these designations are a guarantee that Mustang Bio’s MB-107 will ultimately get FDA approval, but they’re a pretty good indication that a lot of people have confidence they’ll get there.

Charting a new course for stem cell research

/ Kevin McCormack / 1 Comment

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

Celebrating a life that almost didn’t happen

/ Kevin McCormack / 1 Comment
Evie Vaccaro

You can’t look at this photo and not smile. This is Evie Vaccaro, and it’s clear she is just bursting with energy and vitality. Sometimes it feels like I have known Evie all her life. In a way I have. And I feel so fortunate to have done so, and that’s why this photo is so powerful, because it’s a life that almost ended before it had a chance to start.

Evie was born with a rare condition called Severe Combined Immunodeficiency (SCID). Children with this condition lack a functioning immune system so even a simple cold or diaper rash can prove fatal. Imagine how perilous their lives are in a time of COVID-19. These children used to be called “bubble babies” because they were often kept inside sterile plastic bubbles to keep them alive. Many died before their second birthday.

Today there is no need for plastic bubbles. Today, we have a cure. That’s a word we use very cautiously, but in Evie’s case, and the case of more than 40 other children, we use it with pride.

Dr. Don Kohn and a child born with SCID

Dr. Don Kohn at UCLA has developed a method of taking the child’s own blood stem cells and, in the lab, inserting a corrected copy of the gene that caused SCID, and then returning those cells to the child. Because they are stem cells they multiply and renew and replicate themselves, creating a new blood supply, one free of the SCID mutation. The immune system is restored. The children are cured.

This is a story we have told several times before, but we mention it again because, well, it never gets old, and because Evie is on the front and back cover of our upcoming Annual Report. The report is actually a look back on the last 18 months in CIRM’s life, reporting on the progress we have made in advancing stem cell research, in saving and changing lives, and in producing economic benefits for California (billions of dollars in sales revenue and taxes and thousands of jobs).  

Evie’s story, Evie’s photo, is a reminder of what is possible thanks to the voters of California who created CIRM back in 2004. Hers is just one of the stories in the report. I think,  you’ll enjoy reading all of them.

Of course, I might be just a little bit biased.

Living proof science can find a cure

/ Kevin McCormack / 2 Comments

Like many kids, let’s face it, many adults too, Ronav “Ronnie” Kashyap is getting a little bored stuck inside all day during the coronavirus pandemic. This video, shot by his dad Pawash, shows Ronnie trying to amuse himself by pretending to be hard at work.

https://www.instagram.com/p/B_BSQaonFXb/

It’s a lovely moment. It’s also a moment that just a few years ago seemed almost impossible. That’s because Ronnie was born with severe combined immunodeficiency (SCID). SCID kids have no functioning immune system so even a simple infection, such as a cold, can be life-threatening.

Many of those hardest hit by COVID-19 have compromised immune systems. But try fighting the virus if you have no immune system at all. The odds would not be good.

Happily, we don’t have to imagine it because Ronnie is one of around 60 children who have undergone CIRM-supported stem cell/gene therapies that have helped repair their immune system.

In Ronnie’s case he was rushed to UC San Francisco shortly after his birth when a newborn screening test showed he had SCID. He spent the next several months there, in isolation with his parents, preparing for the test. Doctors took his own blood stem cells and, in the lab, corrected the genetic mutation that causes SCID. The cells were then re-infused into Ronnie where they created a new blood supply and repaired his immune system.

How good is his immune system today? Last year his parents, Upasana and Pawash, were concerned about taking Ronnie to a crowded shopping mall for fear he might catch a cold. Their doctor reassured them that he would be fine. So, they went. The doctor was right, Ronnie was fine. However, Upasana and Pawash both caught colds!

Just a few weeks ago Ronnie started pre-school. He loves it. He loves having other kids to play with and his parents love it because it helps him burn off some energy. But they also love it because it showed Ronnie is now leading a normal life, one where they don’t have to worry about everything he does, every person he comes into contact with.

Sounds a bit like how the rest of us are living right now doesn’t it. And the fears that Ronnie’s parents had, that even a casual contact with a friend, a family member or stranger, might prove life-threatening, are ones many of us are experiencing now.

When Ronnie was born he faced long odds. At the time there were only a handful of scientists working to find treatments for SCID. But they succeeded. Now, Ronnie, and all the other children who have been helped by this therapy are living proof that good science can overcome daunting odds to find treatments, and even cures, for the most life-threatening of conditions.

Today there are thousands, probably tens of thousands of scientists around the world searching for treatments and cures for COVID-19. And they will succeed.

Till then the rest of us will have to be like Ronnie. Stay at home, stay safe, and enjoy the luxury of being bored.